NK cells are needed in the body to protect against malignancy and virus infection. Genetic factors in different individuals can affect how NK cells recognize and respond to target cells. However, there is still much to be learned about how genetic differences can actually influence NK cells and their role in virus immunity. This proposal is based on using several new MHC congenic and transgenic mouse strains generated in the PI's laboratory to model the effect(s) of MHC polymorphism on NK cell-mediated virus immunity. The broad long-term objective for the research project seeks to understand how MHC polymorphism imparts its effect on NK-mediated virus immunity, other immune cells and protection from disease in the given hosts. Published and preliminary data implicate multiple mechanisms. A guiding hypothesis for the proposal is that MHC polymorphism can influence membrane-bound inhibitory receptors displayed by NK cells and their capacity to recognize and respond to virus infection. Three specific aims are proposed: Aim 1. To determine the effect of Ly49G2 expression on NK cells needed in MHC-I Dk resistance to MCMV infection. The induction and kinetics of NK cells specifically responding to MCMV infection, and the effect such responses have on DCs and virus specific T cell effector cells will be examined to ascertain the underlying molecular and cellular virus control mechanisms. Aim 2. To determine the effect of inhibitory Ly49G2 receptor expression on NK cells needed in MHC-I Dk resistance to MCMV infection. Preliminary data support a critical role for Ly49G2 in virus resistance. Molecular, cellular and biochemical strategies will be used to examine the receptor and its impact on NK cells. Aim 3. To evaluate the impact of MHC-I Dk on licensing and inhibitory receptor signaling in Ly49G2+ NK cells for highly efficient MCMV resistance, protection of spleen DCs and prompt induction of virus specific CD8+ T cell immunity. Biochemical and genetic strategies will be used to probe inhibitory receptor signaling in normal and inhibitory signaling deficient NK cells, their acquisition of potent antiviral effector activity and their involvement in MHC-I Dk- dependent virus resistance. Relevance The importance and health relevance of the research described in this proposal is related to the establishment of a new mouse model to examine natural killer (NK) cells responding to and controlling virus infection. Achievement of the specific aims in the research proposal will advance our understanding of genetic, molecular and cellular mechanisms used by NK cells to provide early protection against virus infection and to help kindle or elicit virus specific adaptive immune responses needed in the eventual clearance of replicating virus. The research project therefore has the potential to unlock new targets of immune cell mediated therapy to heighten disease resistance and greater understanding of the intricate links between innate and adaptive immunity may be important for vaccine development strategies. PUBLIC HEALTH RELEVANCE: This research proposal uses several new MHC recombinant congenic and transgenic strains of mice generated in the PI's laboratory to model and investigate how MHC polymorphism can regulate NK cell- mediated virus immunity. Three aims are proposed: Aim 1 will delineate the effect of MHC polymorphism on NK and dendritic cell contributions in virus resistance; Aim 2 will examine the effect of an inhibitory Ly49 receptor expressed by NK cells needed in virus resistance; and Aim 3 will study the effect of MHC polymorphism on NK cell education of effector functions which can impact early resistance to virus infection through NK cells and consequently later virus-specific immune responses.